Neurovascular dysfunction substantially contributes to Alzheimer disease. Here, we show that transcriptional profiling of human brain endothelial cells (BECs) defines a subset of genes whose expression is age-independent but is considerably altered in Alzheimer disease, including the homeobox gene MEOX2 (also known as GAX), a regulator of vascular differentiation, whose expression is low in Alzheimer disease. By using viral-mediated MEOX2 gene silencing and transfer, we show that restoring expression of the protein it encodes, GAX, in BECs from individuals with Alzheimer disease stimulates angiogenesis, transcriptionally suppresses AFX1 forkhead transcription factor–mediated apoptosis and increases the levels of a major amyloid-β peptide (Aβ) clearance receptor, the low-density lipoprotein receptor–related protein 1 (LRP), at the blood-brain barrier. In mice, deletion of Meox2 (also known as Gax) results in reductions in brain capillary density and resting cerebral blood flow, loss of the angiogenic response to hypoxia in the brain and an impaired Aβ efflux from brain caused by reduced LRP levels. The link of MEOX2 to neurovascular dysfunction in Alzheimer disease provides new mechanistic and therapeutic insights into this illness.
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This work was supported by US National Institutes of Health (NIH) R37 AG023084 and a Socratech research grant to B.V.Z., NIH grants R43 AG24002 to J.S. and R43 AG23993 to N.C.
J. Sallstrom, N. Chow and R. Bell are Socratech employees, and B.V. Zlokovic, F. Hofman and R. Zidovetzki serve as Socratech consultants. Socratech LLS sponsored transcriptional profiling study and building of the BioBank with primary neurovascular cells. Socratech has an interest in developing new theories for Alzheimer's disease.
TUNEL-positive and AFX1-positive microvessels in Alzheimer disease and age-matched control brains. (PDF 8635 kb)
Vascular reactivity in Gax+/+ and Gax+/− mice. (PDF 533 kb)
Brain capillary length and LRP levels in Ahr−/− mice. (PDF 1021 kb)
Internalization of α2M in BECs with suppressed MEOX2 expression. (PDF 327 kb)
Proteasomal proteolytic activity, transferrin levels and RAP in human BECs. (PDF 422 kb)
Expression of MEF2, ankyrin G, plectin 1 and TINUR in human BECs. (PDF 513 kb)
Aβ does not affect GAX expression in human BECs (PDF 491 kb)
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Vascular Dysfunction in Alzheimer’s Disease: A Prelude to the Pathological Process or a Consequence of It?
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